This invention relates to inhibition of cysteine cathepsins for treating cancer and other human disease states. More particularly the invention relates to the induction of apoptotis cell death in human cancer cells by inhibitors of cysteine cathepsins.
Cathepsins (Cats) belong to the papain superfamily of lysosomal cysteine proteases. Cathepsins are involved in the normal proteolysis and turnover of target proteins and tissues as well as in initiating proteolytic cascades by proenzyme activation and in participating in MHC class II molecule expression. Baldwin (1993) Proc. Natl. Acad. Sci., 90: 6796-6800; Mixuochi (1994) Immunol. Lett., 43:189-193.
However, aberrant cathepsin expression has also been implicated in several serious human disease states. Cathepsins have been shown to be abundantly expressed in cancer cells, including breast, lung, prostate, glioblastoma and head/neck cancer cells, (Kos et al. (1998) Oncol. Rep., 5:1349-1361; Yan et al. (1998) Biol. Chem., 379:113-123; Mort et al. (1997) Int. J Biochem. Cell Biol., 29: 715-720; Friedrick et al. (1999) Eur. J Cancer, 35:138-144) and are associated with poor treatment outcome of patients with breast cancer, lung cancer, brain tumor and head/neck cancer. Kos et al, supra. Additionally, aberrant expression of cathepsin is evident in several inflammatory disease states, including rheumatoid arthritis and osteoarthritis. Keyszer (1995) Arthritis Rheum., 38:976-984.
The molecular mechanisms of cathepsin activity are not completely understood. Recently, it was shown that forced expression of cathepsin B rescued cells from serum deprivation-induced apoptotic death (Shibata et al. (1998) Biochem. Biophys. Res. Commun., 251: 199-203) and that treatment of cells with antisense oligonucleotides of cathepsin B induced apoptosis. Isahara et at. (1999) Neuroscience, 91:233-249. These reports suggest an anti-apoptotic role for the cathepsins that is contrary to earlier reports that cathepsins are mediators of apoptosis. Roberts et al (1997) Gastroenterology, 113: 1714-1726; Jones et al. (1998) Am. J Physiol., 275: G723-730.
Cathepsin inhibitor I Z-Phe-Gly-NHO-Bz (CATI-1) is a selective inhibitor of cathepsin activity. Demuth et al. (1996) Biochem. Biophy. Acta, 1295: 179-186. Little is known on the significance of cathepsin inhibition, especially in the fields of biomedical research and therapeutic drug design. Against this backdrop the present invention has been developed.
The present invention involves the surprising and unexpected discovery that cathepsin inhibitors and methods of use for cathepsin inhibitors trigger cathepsin dependent apoptosis in cancer cells and in cells having aberrant levels of cathepsin.
One aspect of the present invention is a method for inhibiting the growth of tumor cells in a subject by administering to the subject a cathepsin inhibitor. The method can include inducing the tumor cells to become apoptotic.
Another aspect of the invention is a method of treating cancer cells in a subject by administering a therapeutically effective amount of cathepsin inhibitor to the subject. The cancer cells can be solid cancer cells, for example breast cancer and prostate cancer cells, or can be cancer of the white blood cells, for example leukemia.
Another aspect of the invention is a method for inhibiting inflammatory disease in a subject by administering to the subject a cathepsin inhibitor. The inflammatory disease can be rheumatoid arthritis.
Another aspect of the invention is a method for inducing cytotoxicity in a cell by administering a cytotoxic dose of cathepsin inhibitor to the cell.
Another aspect of the invention is a pharmaceutical composition having a substantially purified cathepsin inhibitor and a pharmaceutically acceptable carrier.
Another aspect of the invention is a method for inhibiting growth of a tumor cell by making a recombinant vector that expresses a cathepsin inhibitor and administering the recombinant vector to the tumor cell.
Finally, another aspect of the invention is a method for inducing apoptosis in a cell by expressing a heterologous nucleic acid sequence encoding the cathepsin inhibitory peptide in a host cell having enhanced cathepsin activity as compared to control host cells.